AU2005310888B2

AU2005310888B2 - Compositions for combating beta-lactamase-mediated antibiotic resistance using beta-lactamase inhibitors useful for injection

Info

Publication number: AU2005310888B2
Application number: AU2005310888A
Authority: AU
Inventors: Manu Chaudhary
Original assignee: Venus Remedies Ltd
Current assignee: Venus Remedies Ltd
Priority date: 2004-12-02
Filing date: 2005-11-28
Publication date: 2011-01-06
Anticipated expiration: 2025-11-28
Also published as: UA91204C2; RU2397768C2; NZ555075A; US20130023512A1; AU2005310888A1; RU2007124325A; EP1841432A1; DE602005022939D1; US8273732B2; WO2006059344B1; WO2006059344A1; DK1841432T3; JP5269415B2; KR101244362B1; ATE476981T1; US20100160277A1; EP1841432B1; BRPI0517128A; US9012442B2; KR20070067189A

Abstract

The invention describes a composition for combating beta-lactamase-mediated antibiotic resistance using beta-lactamase inhibitor useful for injection, capable of pharmaceutical application. The invention relates to pharmaceutical composition containing ceftriaxone (normally as ceftriaxone sodium) and sulbactam (normally as sulbactam sodium). Such compositions are found to be useful for intramuscular or intravenous administration as antibiotics for hospitalized patients with serious infections. Specifically, this invention relates to a pharmaceutical composition further including an aminocarboxylic acid chelating agent, for example, ethylenediaminetetraacetic acid (EDTA), or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions of this invention have been found normally to enhance resistance to particulate formation in solutions to be administered parenterally. The invention also gives details of the dosage forms stored in sealed containers to be reconstituted before use. The invention also gives a process to manufacture these compositions. The invention gives a method of treating a subject having a condition or disorder, wherein a treatment with ceftriaxone sodium and sulbactam sodium is indicated.

Description

WO 2006/059344 PCT/IN2005/000382 COMPOSITIONS FOR COMBATING BETA-LACTAMASE-MEDIATED 5 ANTIBIOTIC RESISTANCE USING BETA-LACTAMASE INHIBITORS USEFUL FOR INJECTION FIELD OF THE INVENTION 10 The invention relates to pharmaceutical compositions containing ceftriaxone (normally as ceftriaxone sodium) and sulbactam (normally as sulbactarn sodium) commercially available as ceftriaxone sodium and sulbactam sodium. Such compositions are found to be useful for intramuscular or intravenous administration as antibiotics for hospitalized patients with serious 15 infections specifically due to beta lactamase producing bacterial strains. This invention relates to a pharmaceutical compositions further including an aminocarboxylic acid chelating agent, for example, ethylene diamine tetraacetic acid (EDTA), or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions described herein normally have been found to enhance resistance to particulate formation in solutions to be administered parenterally. 20 BACKGROUND OF THE INVENTION There have been increased incidence of bacterial resistance to 0 lactam antibiotics in the past 15 years, in spite of the introduction of potent new antibacterial agents belonging to novel 25 chemical classes such as penems, cephems, oxacephems, monobactams, and carbaphenems. Del Carmen Rodriguez M., et. al. (2004), in their paper, "Phenotypic confirmation of extended spectrum beta-lactamases (ESBL) in clinical isolates of Escherichia coli and Klebsiella pneumoniae at the San Juan Veterans Affairs Medical Center",have discussed about ESBLs as 30 an important mechanism of resistance to B-lactam antibiotics in gram-negative bacteria (GNB). They are enzymes that hydrolyze older B-lactam antibiotics as well as broad-spectrum cephalosporins and monobactams. Jacoby GA., (1994), in his paper "Genetics of extended-spectrum beta-lactamases" described 35 that bacteria have adapted resistance to aztreonam, cefotaxime, ceftazidime, ceftriaxone and other oxyimino-beta-lactams, by altering existing plasmid-mediated class A and class D beta 1 WO 2006/059344 PCT/IN2005/000382 lactamases . Niemeyer DM., (1994), in his paper, "Regulation of beta-lactamase induction in gram-negative bacteria : a key to understanding the resistance puzzle," discusses that infections caused by 5 drug-resistant microorganisms have posed a medical challenge since the advent of antimicrobial therapy. With the emergence of resistant strains, new antibiotics were available and introduced with great success until this decade. The appearance of multiresistant microorganisms poses a real and immediate public health concern. 10 Danziger LH. and Pendland SL, (1995) in their paper, "Bacterial resistance to beta-lactam antibiotics." have found that the most commonly prescribed antimicrobials in the United States are the beta-lactam antibiotics, and the most common mechanism of bacterial resistance to these agents is inactivation by beta-lactamase. 15 Medeiros AA., (1997), in his research paper, "Evolution and dissemination of beta-lactamases accelerated by generations of beta-lactam antibiotics," has stated that beta-lactamases are the principal mechanism of bacterial resistance to beta-lactam antibiotics. Ritter E., et al, (1992) in their paper (article in German) "Outbreak of a nosocomial infection of 20 SHV2-beta-lactamase-containing Klebsiella pneumonia strains in an operative intensive care unit." stated that resistant strains of Klebsiella pneumoniae produced type SHV2-broad spectrum betalactamase. Thus, the bacteria were resistant to third-generation cephalosporins, such as cefotiam, cefotaxime and ceftriaxone and also to aminoglycosides and acylaminopenicillins. 25 S. J. Cavalieri, et al, (1991) in their paper, "Influence of beta-lactamase inhibitiors on the potency of their companion drug with organisms possessing class I enzymes," undertook a study which was designed to assess the ability of sulbactam and clavulanate to induce beta lactamases in two strains each of Enterobacter cloacae, Citrobacter freundii, Serratia 30 marcescens, and Pseudomonas aeruginosa both in vitro and in vivo. The data suggest that beta lactamase inhibitors can influence the in vivo potency of their companion drug. Ghatole M., et at, (2004), in their paper, "Correlation of extended spectrum beta-lactamases production with cephalosporin resistance in gram negative bacilli", discussed that beta 2 WO 2006/059344 PCT/IN2005/000382 lactamase production is an important mechanism of developing resistance to beta lactam group of antibiotics. Cephlosporins with extended spectrum of activity and stability were introduced to overcome this resistance, but soon production of extended spectrum beta lactamase (ESBLs), which are inducible in nature was reported. 5 Lopez-Hernandez S. et al, (1999) in their paper, "In vitro activity of beta-lactam agents and beta-lactamase inhibitors in clinical isolates of Acinetobacter baumannii", compared the in vitro activity of betalactam agents, (ampicillin, piperacillin and ticarcillin), betalactamase inhibitors (clavulanic acid, sulbactam and tazobactam) alone and in combination with 10 betalactam agents (amoxicillin - clavulanic acid, ampicillin-sulbactam, piperacillin-tazobactam and ticarcillin-clavulanic) against 156 clinical isolates of A. baumannii. Sulbactam was the only betalactamase inhibitor which showed good in vitro activity, with a low MIC(50) and MIC (90) ( and 32 mg/l, respectively) similar to ampicillin/sulbactam (2 and 16 mg/l, respectively). Sulbactam could be good therapeutic alternative for the treatment of multiresistant A. 15 baumannii infections. Sadar HS., et al, (2000) in their paper, "Comparative evaluation of the in vitro activity of three combinations of beta-lactams with beta-lactamase inhibitors: piperacillin/tazobactam, ticarcillin/clavulanic acid and ampicillin/sulbactam", found that ticarcillin/clavulanic acid was 20 active against 85.8% of the Enterobacteriaceae, while ampicillin/sulbactam inhibited 83.2% of the samples. Finegold SM, (1999) in his paper, "In vitro efficacy of beta-lactam/beta-lactamase inhibitor combinations against bacteria involved in mixed infections", found that the mixed infections 25 are usually caused by a relatively limited range of bacteria, with the anaerobes and opportunistic pathogens contributing to their severity. In order to make the best therapeutic choice for a patient with a life-threatening infection, which is probably of mixed etiology, clinicians must be aware of the organisms that are likely to be involved, and the fact that most of them will produce beta-lactamase. Of the options available for empiric therapy, the beta 30 lactam/beta-lactamase inhibitor combinations represent a good choice. Their antibacterial spectra include both aerobic and anaerobic pathogens. It is clear that there is a need to provide an inexpensive antibiotic formulation that will be effective against the increasing variety of E lactamase-producing bacterial strains. There is 3 WO 2006/059344 PCT/IN2005/000382 also a need for such formulations to be provided in parenterally administrable form. There is also a need to develop antibiotic formulations that will not lead to rapid emergence of resistant bacterial strains. 5 OBJECTS AND ADVANTAGES OF THE PRESENT INVENTION Accordingly, the objects and advantages of the present invention are described as below: An object of the present invention is to provide an antibiotic formulation effective against L 10 lactamases-producing bacterial strains. Another object of the present invention is to provide antibiotic formulation against L lactamases-producing bacterial strains in parenterally administrable forms. 15 Yet another object of the present invention is to develop antibiotic formulations that does not lead to rapid emergence of resistant bacterial strains. A still further object of the present invention is to provide therapeutically safe dose through a process of making antibiotic formulations effective against E lactamase. 20 Another object of present invention is to enhance the total bactericidal range of existing ceftriaxone sodium injection. SUMMARY OF THE INVENTION 25 The invention describes a composition for combating beta-lactamase-mediated antibiotic resistance using beta-lactamase inhibitor useful for injection, capable of pharmaceutical application. 30 The invention relates to pharmaceutical composition containing ceftriaxone (normally as ceftriaxone sodium) and sulbactam (normally as sulbactam sodium). Such compositions are found to be useful for intramuscular or intravenous administration as antibiotics for hospitalized patients with serious infections specifically due to beta lactamase producing bacterial strains. This invention relates to a pharmaceutical composition further including an 4 WO 2006/059344 PCT/IN2005/000382 aminocarboxylic acid chelating agent, for example, ethylenediaminetetraacetic acid (EDTA), or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions of this invention have been found normally to enhance resistance to particulate formation in solutions to be administered parenterally. The invention also gives details of the dosage forms stored in sealed 5 containers to be reconstituted before use. The invention also gives a process to manufacture these compositions. The invention gives a method of treating a subject having a condition or disorder, wherein a treatment with ceftriaxone sodium and/or sulbactam sodium is indicated. DETAILEDED DESCRIPTION OF THE INVENTION 10 The present invention provides formulations containing ceftriaxone (or a pharmaceutically acceptable salt thereof, referred to hereafter as 'a ceftriaxone salt', such as cetriaxone sodium) and sulbactam (or a pharmaceutically acceptable salt thereof, referred to hereafter as 'a sulbactam salt', such as sulbactam sodium) that can be used in the treatment of moderate to 15 severe infections caused by ceftriaxone resistant beta-lactamase-producing strains of microorganisms which are made susceptible by the addition of sulbactam in conditions such as lower respiratory tract infections ,acute bacterial ottitis media , skin and skin structure infections ,urinary tract infections (complicated and uncomplicated), pelvic inflammatory disease , bacterial septicemia, bone and joint infections , intra-abdominal infections , meningitis 20 , surgical prophylaxis and pre-post operatively. The different embodiments of the present invention are described below in detail. This invention basically provides a composition for combating beta-lactamase-mediated antibiotic resistance using beta-lactamase inhibitor, useful for injection, capable of 25 pharmaceutical application, comprising: (a) ceftriaxone or a pharmaceutically acceptable salt thereof, and (b) sulbactam or a pharmaceutically acceptable salt thereof, in predetermined weight ratios. It is desirable to minimize the particulate formations that occur in the pharmaceutical 30 compositions upon reconstitution. The particulates consist of mobile, randomly sourced, extraneous substances other than gas bubbles, that cannot be quantified by chemical analysis due to small amount of material and due to its heterogeneous composition. Particulate inhibitors such as an aminocarboxylic acid chelating agent is optionally used in the present invention. Surprisingly it has been found by the inventor that their incorporation reduces the 5 WO 2006/059344 PCT/IN2005/000382 particulate formation in the reconstituted formulation. The optional chelating agent is selected from a group comprising ethylene diamine tetraacefic acid (EDTA) and salts thereof, diethylene triamine pentaacetic acid (DTPA), hydroxyethylene diamine triacetic acid (HEDTA), nitrilo triacetic acid (NTA) or a pharmaceutically acceptable salt thereof (normally 5 as a sodium salt). The preferred chelating agent is EDTA and salts thereof, preferably edetate disodium as defined in the United States Pharmacopoeia, that can be used with this embodiment. In the reconstituted form, the amount of EDTA used in this embodiment is in the range of about 0.002 mg/ml to about 10 mg/ml, or more preferably, in the range of 0.003 to 2 mg/ml. 10 This composition further comprises a pharmaceutically acceptable tonocity adjusting agent, thereby rendering the composition physiologically isotonic. In this composition the predetermined weight ratio of the ceftriaxone or of the pharmaceutically acceptable salt thereof, to the sulbactam or to the pharmaceutically acceptable salt thereof, is in 15 the range from about 4:1 to about 1:4 respectively, preferably in the range from about 3:1 to about 1:3 respectively, more preferably in the range from about 2:1 to about 1:2 respectively. The pharmaceutically acceptable salt of ceftriaxone is sodium salt thereof, such as ceftriaxone sodium. 20 The ceftriaxone sodium is (6R, 7R)-7-[2-(2-aniino-4-thiazolyl)glyoxylamido]-8-oxo-3 [[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl]-5-thia-1 azabicyclo[4.2.0]oct-2-ene-2-carboxyalic acid, 7 2 -(Z)-(O-methyloxime), disodium salt, sesquaterhydrate which is in the form of white to yellowish-orange crystalline powder, the 25 powder being readily soluble in water, sparingly soluble in methanol and very slightly soluble in ethanol. The ceftriaxone sodium has tapped density in the range from about 0.5 g/ml to 0.6 g/ml and moisture content is in the range from about 8% to about 11% w/w, of the compound. 30 The pH of solution of the ceftriaxone sodium is in the range from about 6 to about 8, where the solution contains one part of the compound in 10 parts, of solution . In this composition the pharmaceutically acceptable salt of the sulbactam is sodium salt 6 WO 2006/059344 PCT/IN2005/000382 thereof, such as sulbactam sodium. The sulbactam sodium is sodium (2S,5R)-3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo(3.2.0) heptane-2-carboxylate 4, 4-dioxide which is in the form of white to off-white dry powder for 5 reconstitution, this powder of the sulbactam being freely soluble in water or dilute acids, sparingly soluble in acetone, ethyl acetate or chloroform. The moisture content of the sulbactam sodium is less than about 1% w/w of the compound. 10 The particulate formation inhibitor comprises at least one compound selected from the group of ethylene diamine tetraacetic acid (EDTA), diethylene triamine penta-acetic acid (DTPA), hydroxyethylene diamine triacetic acid (HEDTA), nitrilo triocetic acid (NTA), and the pharmaceutically acceptable salts of any of these compounds, preferably sodium salts. 15 This particulate formation inhibitor is preferably the EDTA. The composition of invention is a sterile blend of the ceftriaxone sodium and the sulbactam sodium optionally with particulate formation inhibitor. 20 The sterile blend comprises the ceftriaxone sodium and the sulbactam sodium in weight ratios in the range of about 4:1 to about 1:4 respectively, preferably from about 3:1 to about 1:3 respectively and more preferably from about 2:1 to 1:2 respectively. The reconstituted solution of the composition of invention has pH in the range from about 5 to 25 8. The tonocity adjusting agent mentioned earlier is either sodium chloride or dextrose which may be pre-blended with the composition or may be used during reconstitution or at the time of infusion. 30 The total sodium content of the ceftriaxone sodium and the sulbactam sodium is in the range from about 16.5 mg (0.719 mEq) to about 264.6 mg (11.48 mEq) of sodium. The EDTA is present in the range from about 0.002 mg/ml to about 10 mg/ml of solution after 7 WO 2006/059344 PCT/IN2005/000382 reconstitution, and preferably the EDTA is in the range from about 0.003 mg/mil to about 2 mg/ml of solution after reconstitution. According to yet another embodiment of the present invention, the required amount of the 5 pharmaceutical composition disclosed herein is provided in a sealed airtight container which is selected from a group comprising a vial, an ampoule, a syringe, a packet, a pouch and an auto injector. These containers can contain the compositions disclosed in this invention in volumes of a single dose or in volumes of multiple doses up to 10. The interior space of the sealed airtight container comprises a fill volume occupied by the formulation of the present invention 10 and a headspace volume occupied aseptically by an inert-gas-limited micro-atmosphere, which micro-atmosphere comprises essentially of one or more inert gases selected from the group consisting of noble gases and nitrogen, such that the ratio of the fill volume to headspace volume is not less than 1:1. 15 The pharmaceutically effective dosage of the composition, in the form of the concentrate of the dose, is provided in a sealed airtight container, wherein the container has a head space volume sufficient for introduction of appropriate volume of an aqueous solvent/ compatible diluent selected from a group of sterile water for injection, bacteriostatic water for injection and isotonic sterile sodium chloride solution sufficient to form an appropriate reconstituted 20 solution of the composition. In case of unit/multiple dose of the composition, the pharmaceutically effective dose is provided in a sealed airtight container, wherein the container has a head space volume sufficient for introduction of appropriate volume of an aqueous solvent. Unit/multiple dose is in 25 the form of an appropriate reconstituted solution of the composition. For use as an injection, the composition is provided in the form of a sterile dry powder, in a sealed airtight container, to form a pharmaceutically acceptable required fixed dose combination for reconstitution prior to intramuscular or intravenous administration for the 30 treatment of the bacterial infections. As another alternative, the composition is provided in a sealed container such as transparent glass vial capped with appropriate halogenated stopper and seal, and is used for reconstitution for intramuscular or intravenous administration for the treatment of the bacterial infections. 8 WO 2006/059344 PCT/IN2005/000382 When the composition is provided in a reconstituted form in a sealed airtight container, the interior space of the container comprises a fill volume occupied by the composition in reconstituted form and a head space volume occupied aseptically by an inert-gas-limited micro 5 atmosphere, which comprises essentially one or more inert gas as selected from the group consisting of noble gases and nitrogen, preferably nitrogen, volume of the nitrogen gas being not more than 5% of the head space volume, and wherein ratio of said fill volume to the head space volume is not less than 1:1. 10 As one alternative, the ceftriaxone sodium and the sulbactam sodium are present in pharmaceutically effective single unit dose, in the sealed container. As another alternative the ceftriaxone sodium and sulbactam sodium are present in pharmaceutically effective amount corresponding to about 1 to about 10 unit doses, in the 15 sealed container. It should be noted that this composition is filled in the sealed container aseptically under inert gas blanket. 20 This invention also provides a method of treating a subject, having a condition or disorder, wherein a treatment with ceftriaxone sodium and/or sulbactam sodium is indicated, which method comprises parenterally administering therapeutically effective amount of the composition. 25 This invention also provides a method of treatment or control of bacterial infections in mammals, comprising a therapeutically effective amount of composition. As one alternative the composition comprises: (a) the ceftriaxone or the pharmaceutically acceptable salt thereof, is present in an 30 amount of about 2 g, calculated as ceftriaxone free acid, (b) the sulbactam or the pharmaceutically acceptable salt thereof, is present in an amount in the range from about 1 g to about 2 g, calculated as sulbactam free acid, (c) the composition further comprises optionally an amount of about 2 mg of 9 WO 2006/059344 PCT/IN2005/000382 EDTA, and (d) the composition being reconstituted with about 20 ml of water for injection. In this composition the total amount of sodium content of the ceftriaxone sodium and the sulbactam sodium is about 264.6 mg with 11.48 mEq of sodium. 5 As another alternative, the composition comprises: (a) the ceftriaxone or said pharmaceutically acceptable salt thereof, is present in an amount of about 1 g, calculated as ceftriaxone free acid, (b) the sulbactam or said pharmaceutically acceptable salt thereof, is present in an 10 amount in the range from about 0.5 g to about 1 g, calculated as sulbactam free acid, (c) the composition further comprises optionally an amount of about 1 mg of EDTA, and (d) the composition being reconstituted with about 10 ml of water for injection. 15 In this composition the amount of sodium content of the ceftriaxone sodium and the sulbactam sodium is about 132.3 mg with 5.74 mEq of sodium. As still another alternative, the composition comprises: (a) the ceftriaxone or said pharmaceutically acceptable salt thereof, is present in an 20 amount of about 0.5 g, calculated as ceftriaxone free acid, (b) the sulbactam or said pharmaceutically acceptable salt thereof, is present in an amount in the range from about 0.25 g to about 0.5 g, calculated as sulbactam free acid, (c) the composition further comprises optionally an amount of about 0.5 mg of 25 EDTA, and (d) the composition being reconstituted with about 5 ml of water for injection. In this composition the total amount of sodium content of the ceftriaxone sodium and the sulbactam sodium is about 66.15 mg with 2.87 mEq of sodium. 30 As further alternative, the composition comprises: (a) the ceftriaxone or the pharmaceutically acceptable salt thereof, is present in an amount of about 0.25 g, calculated as ceftriaxone free acid, (b) the sulbactam or the pharmaceutically acceptable salt thereof, is present in an amount in the range from about 0.125 g to about 0.25 g, calculated as sulbactam 10 WO 2006/059344 PCT/IN2005/000382 free acid, (c) the composition further comprises optionally an amount of about 0.25 mg of EDTA, and (d) the composition being reconstituted with about 4 ml of water for injection. 5 In this composition the total amount of sodium content of the ceftriaxone sodium and the sulbactam sodium is about 33.075 mg with 1.435 mEq of sodium. As yet further alternative, the composition comprises: (a) the ceftriaxone or the pharmaceutically acceptable salt thereof, is present in an 10 amount of about 0.125 g, calculated as ceftriaxone free acid, (b) the sulbactam or the pharmaceutically acceptable salt thereof, is present in an amount in the range from about 0.0625 g to about 0.125 g, calculated as sulbactam free acid, (c) the composition further comprises optionally an amount of about 0.125 mg of 15 EDTA, and (d) the composition being reconstituted with about 2 ml of water for injection. In this composition the total amount of sodium content of the ceftriaxone sodium and the sulbactam sodium is about 16.535 mg with 0.717 mEq of sodium. 20 For parenteral administration, the composition is in the form of sterile powder, which is reconstituted by addition of a compatible diluent selected from a group of sterile water for injection, bacteriostatic water for injection and isotonic sterile sodium chloride solution,prior to parenteral. 25 This invention also provides a process for preparing a composition for combating beta lactamase-mediated antibiotic resistance using beta-lactamase inhibitors useful for injection, suitable for pharmaceutical application, comprising the steps of: 30 (a) sterile filling/blending two active ingredients, first active ingredient being the ceftriaxone or the pharmaceutically acceptable salt thereof and second ingredient being the sulbactam or the pharmaceutically acceptable salt thereof, optionally adding a particulate formation inhibitor (EDTA) or a pharmaceutically acceptable salt thereof and /or tonocity adjusting agent, the 11 WO 2006/059344 PCT/IN2005/000382 sterile filling/blending being continued for a period ranging from about 1 hour to about 4 hours, (b) proportioning the sterile fill/ blend of step (a), aseptically to get desired dose in weight ratio of said first active ingredient to said second active ingredient in the 5 range from about 4:1 to about 1:4 respectively, preferably from about 3:1 to about 1:3 respectively, more preferably in the range of about 2:1 to about 1:2 respectively, and (c) capping aseptically with pre-post inert gassing. 10 While the above description contains many specificities, these should not be construed as limitations in the scope of the invention but as exemplifications of embodiments thereof. Many other variations are possible. Accordingly, the scope of the invention should be determined not by the embodiments illustrated, but by the appended claims and their legal equivalents. 12

Claims

1. A pharmaceutical composition for combating beta lactamase mediated antibiotic resistance, said pharmaceutical composition comprising: 5 a beta lactam antibiotic, wherein said betalactam antibiotic is a ceftriaxone or a pharmaceutically accepted salt of ceftriaxone; a beta lactamase inhibitor, wherein said beta lactamase inhibitor is a 10 sulbactam or a pharmaceutically accepted salt of sulbactam; said beta lactamase inhibitor and said beta lactam antibiotic are present in said formulation in a weight ratio of 1:4 to 4:1; and 15 a particulate formation inhibitor, said particulate formation inhibitor comprising an ethylene diamine tetraacetic acid or pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1 wherein, said beta lactamase 20 inhibitor and said beta lactam antibiotic are present in said formulation in a weight ratio of 2:1.

3. The pharmaceutical composition of either claim 1 or 2, wherein said pharmaceutical composition further comprises a pharmaceutically acceptable 25 tonocity adjusting agent, wherein said pharmaceutically acceptable tonocity adjusting agent is selected from the group consisting of a sodium chloride and a dextrose, and 30 said pharmaceutically acceptable tonocity adjusting agent is pre-blended with said pharmaceutical composition so that said pharmaceutical 13 composition is physiologically isotonic when made up in solution.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein said beta lactamase inhibitor, said beta lactam antibiotic and said ethylene diamine 5 tetraacetic acid disodium salt or pharmaceutically acceptable salt thereof each are present either as a powder or a solution.

5. The pharmaceutical composition of either claims 1 or 2 wherein the composition comprises a water based solution comprising 0.002 mg to 10 mg of 10 said ethylene diamine tetraacetic acid or pharmaceutically acceptable salt thereof per ml.

6. The pharmaceutical composition of claim 5 wherein the pharmaceutically further comprises a pharmaceutically acceptable tonocity adjusting agent 15 selected from the group consisting of a sodium chloride and a dextrose, thereby rendering the composition isotonic.

7. The pharmaceutical composition of either claim 5 or 6, wherein said beta 20 lactamase inhibitor is a sulbactam sodium and said beta lactam antibiotic is a ceftriaxone sodium. 25

8. The pharmaceutical composition of claim 7, wherein said pharmaceutical composition comprises: 2 gm of said ceftriaxone sodium calculated as ceftriaxone free acid; 1 gm of said sulbactam sodium calculated as sulbactam free acid; and 30 2 mg of said ethylene diamine tetraacetic acid or a pharmaceutically acceptable salt thereof, 14 reconstituted with about 20 ml of water and wherein total amount of sodium content of said ceftriaxone sodium and sulbactam 5 sodium in said pharmaceutical composition is about 264.6 mg with 11.48 mEq of sodium.

9. The pharmaceutical composition of claim 7, wherein said pharmaceutical composition comprises: 10 1 gm of said ceftriaxone sodium calculated as ceftriaxone free acid; 0.5 gm of said sulbactam sodium calculated as sulbactam free acid; and 1 mg of said ethylene diamine tetraacetic acid or a pharmaceutically acceptable salt thereof, 15 reconstituted with about 10 ml of water and wherein total amount of sodium content of said ceftriaxone sodium and sulbactam sodium in said pharmaceutical composition is about132.3 mg with 5.74 mEq of 20 sodium.

10.The pharmaceutical composition of claim 7, wherein said pharmaceutical composition comprises: 25 0.5 gm of said ceftriaxone sodium calculated as ceftriaxone free acid; 0.25 gm of said salbactam sodium calculated as sulbactam free acid; and 0.5 mg of said ethylene diamine tetraacetic acid or pharmaceutically acceptable salt thereof, 30 reconstituted with about 5 ml of water and 15 wherein total amount of sodium content of said ceftriaxone sodium and sulbactam sodium in said pharmaceutical composition is about 66.15 mg with 2.87 mEq of sodium. 5

11.The pharmaceutical composition of claim 7, wherein said pharmaceutical composition comprises: 0.25 gm of said ceftriaxone sodium calculated as ceftriaxone free acid; 10 0.125 gm of said sulbactam sodium calculated as sulbactam free acid; and 0.25 mg of said ethylene diamine tetraacetic acid or pharmaceutically acceptable salt thereof, reconstituted with about 4 ml of water and 15 wherein total amount of sodium content of said ceftriaxone sodium and sulbactam sodium in said pharmaceutical composition is about 33.075 mg with 1.435 mEq of sodium. 20

12. The pharmaceutical composition of claim 7, wherein said pharmaceutical composition comprises: 0.125 gm of said ceftriaxone sodium calculated as ceftriaxone free acid; 0.0625 gm of said sulbactam sodium calculated as sulbactam free acid; 25 and 0.125 mg of said ethylene diamine tetraacetic acid or pharmaceutically acceptable salt thereof, wherein said pharmaceutical composition is reconstituted with about 2 ml of water 30 and 16 wherein total amount of sodium content of said ceftriaxone sodium and sulbactam sodium in said pharmaceutical composition is about 16.535 mg with 0.717 mEq of sodium. 5

13. A process to prepare a pharmaceutical composition for combating beta lactamase mediated antibiotic resistance comprising a beta lactamase inhibitor, a beta lactam antibiotic, and a particulate formation inhibitor, being ethylene diamine tetraacetic acid or pharmaceutically acceptable salt thereof, 10 said process comprising the steps of: a sterile blending of a first active ingredient, being the beta lactam antibiotic, and a second ingredient, being the beta lactamase inhibitor 15 together with said ethylene diamine tetraacetic acid or pharmaceutically acceptable salt thereof, wherein said first active ingredient is said ceftriaxone sodium or a pharmaceutically acceptable salt thereof and said second active ingredient is said sulbactam sodium or a pharmaceutically 20 acceptable salt thereof, and continuing said sterile blending for a period ranging from 1 hr to 4 hr; proportioning said sterile blend aseptically to obtain a dose comprising a weight ratio of said first active ingredient to said second active 25 ingredient in the range of 1: 4 to 4:1; and capping said dose aseptically in a container with pre-post inert gassing.

14. The method of claim 13 wherein, said beta lactamase inhibitor and said 30 beta lactam antibiotic are present in said formulation in a weight ratio of 2:1 17